Dolutegravir is chemically known as (4R,12aS)-9-{[(2,4-difluorophenyl)methyl]carbamoyl}-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1′,2′:4,5]pyrazino [2,1-b][1,3]oxazin-7-olate and represented by the following structural formula;

Dolutegravir (DTG, GSK1349572) is an integrase inhibitor being developed for the treatment of human immunodeficiency virus (HIV)-1 infection. Sodium salt of dolutegravir was recently approved by FDA and marketed under the brand name of TIVICAY by ViiV Healthcare and manufactured by GlaxoSmithKline. TIVICAY is administered orally as a tablet of 50 mg strength.
Tivicay is a human immunodeficiency virus type 1 (HIV-1) integrase strand transfer inhibitor (INSTI) indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection.
Dolutegravir and process for its preparation were first described in U.S. Pat. No. 8,129,385. However this patent does not discloses any characteristic details of dolutegravir or its salts such as sodium.
WO2010068253 publication discloses anhydrous and monohydrate crystalline form of dolutegravir sodium characterized by PXRD and IR spectrum. Anhydrous dolutegravir sodium obtained by treating the solution of dolutegravir in ethanol with aqueous sodium hydroxide at 80° C.; whereas the monohydrate form was obtained by dissolving the anhydrous dolutegravir sodium in THF-water followed by treatment with aqueous sodium hydroxide. This publication further discloses the crystalline form of dolutegravir free acid along with its PXRD.
WO 2013038407 publication discloses amorphous form of dolutegravir sodium, process for its preparation and pharmaceutical composition comprising the same.
IP.com journal, ID No: IPCOM000238311D discloses the crystalline form of dolutegravir sodium characterized by PXRD, which is obtained by treating dolutegravir in tetrahydrofuran with aqueous sodium hydroxide at reflux temperature.
WO2015092752 publication discloses crystalline Form-M1 of dolutegravir sodium and process for its preparation.
WO2015118460 publication discloses crystalline Form-M2. Form-M3 and Form-M4 of dolutegravir sodium and process for their preparation.
WO2015138933 publication discloses crystalline Form-II, Form-III, Form-IV, Form-V, Form-VI, Form-VII, Form-VIII, Form-IX, Form-X and Form-XI of dolutegravir sodium, process for their preparation, pharmaceutical composition comprising them and uses thereof.
WO2015139591 publication discloses polymorphic Form-A, Form-B, Form-C, Form-D and Form-E of dolutegravir sodium and pharmaceutical composition comprising them.
WO2016016279 publication discloses crystalline Form-HxA, Form-Hy1B and Form-SETOH,H2O of dolutegravir sodium, process for their preparation and pharmaceutical composition comprising them.
WO2016102078 publication discloses crystalline form of dolutegravir sodium 1,2-propylene glycol solvate, process for its preparation and pharmaceutical composition comprising the same.
Our co-pending IN application number 3105/CHE/2015 discloses crystalline form of dolutegravir sodium designated as Form-L1, Form-L2, Form-L3, Form-L4, Form-L5, Form-L6, Form-L7 and Form-L8, amorphous form of dolutegravir, solid dispersion of dolutegravir sodium with one or more pharmaceutically acceptable excipient and crystalline benzyltrimethyl ammonium salt of dolutegravir.
Polymorphism is the occurrence of different crystalline forms of a single compound and it is a property of some compounds and complexes. Thus, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as different solubility profiles, different melting point temperatures and/or different x-ray diffraction peaks. Since the solubility of each polymorph may vary, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with predictable solubility profiles. It is desirable to investigate all solid state forms of a drug, including all polymorphic forms and solvates, and to determine the stability, dissolution and flow properties of each polymorphic form.
Dolutegravir is one of the important drugs available in the market for the treatment of human immunodeficiency virus (HIV)-1 infection. Hence it's important to discover new polymorphic forms of dolutegravir and its salt, which may provide a new opportunity to improve the performance characteristics of a pharmaceutical product. Hence the main object of the present invention is to provide novel polymorphic forms of dolutegravir and salts thereof, especially sodium.